Because it has proven difficult to establish clearly the role of energy metabolism in the control of normal feeding, this application proposes behavioral, physiological, and genetic studies of the mechanisms by which hepatic metabolism controls normal spontaneous feeding in rats. Our hypothesis is that hepatic metabolic consequences of food ingestion generate negative feedback signals that reach the brain via vagal afferent neurons and act in the brain to terminate ingestion and limit meal size (i.e., produce satiation). Furthermore, we hypothesize that the relevant metabolic events result from the biochemical integration of hepatocellular glucose and fatty acid utilization and that they are modulated by liver glycogen content. Seven specific aims are proposed to determine: (1) whether changes in hepatocellular ATP energy status are sufficient to affect spontaneous meal size or meal number; whether hepatocellular utilization of carbohydrate or medium-chain fatty acids is sufficient to reduce spontaneous meal size or meal number; (2) whether changes in hepatocellular utilization of carbohydrate or medium-chain fatty acids are sufficient to affect spontaneous meal size or meal number; (3) whether hepatic glycogen content modulates the hepatocellular metabolic control of spontaneous feeding; (4) the role of the vagus nerve in hepatocellular metabolic control of spontaneous feeding; (5) which areas of the brainstem and hypothalamus are activated by manipulations of hepatocellular metabolic controls of spontaneous feeding; (6) whether there are estradiol-sensitive sex differences in hepatocellular metabolic controls of spontaneous feeding; and (7) if there are phenotypic differences in the hepatocellular control of meal size in transgenic rats with inducible over-expressions (knock in) of key enzymes of the putative hepatocellular metabolic pathways affecting meal size. Because disordered eating is a central feature anorexia nervosa, bulimia nervosa, and obesity and because metabolic controls of food intake may be disturbed in syndromes such as NIDDM, the proposed studies should contribute new basic physiological knowledge that may facilitate advances in understanding and treating human health problems. Work on this project will be done as a consortium to capitalize on the unique expertise of the PI at Swiss Federal Institute for Technology, Zurich, Switzerland, and the co-PI, at Weill Medical College of Cornell University, White Plains, NY.